Abstract
Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti‐MMP9 antibody (αMMP9) was evaluated in combination with nab‐paclitaxel (NPT)‐based standard cytotoxic therapy in pre‐clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA‐Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2‐week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six‐week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti‐MMP9 antibody increased the levels of tumour‐associated IL‐28 (1.5‐fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti‐MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti‐MMP9 antibody can exert specific stroma‐directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most ag‐ gressive tumours and is characterized by extensive local invasion, metastasis to distant organs and high rate of treatment failure after both local and systemic therapies.[1]
The failure of the broad‐spectrum Matrix metalloproteinase 9 (MMP9) inhibitors in clinical tri‐ als was mainly correlated with dose‐limiting side effects, a narrow therapeutic window as Matrix metalloproteinases (MMPs) play a critical role in homeostatic processes 14 and general lack of efficacy in advanced tumour bur‐ den settings.[15,16]
Recent studies have shown an essential role of MMP9 in tumour progression of many solid tu‐ mours including PDAC through modulating stromal tumour micro‐ environment promoting angiogenesis, metastasis, epithelial‐mesenchymal transition (EMT) and drug resistance.[9,10,18,25,33]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most ag‐ gressive tumours and is characterized by extensive local invasion, metastasis to distant organs and high rate of treatment failure after both local and systemic therapies.[1]. A broad‐spec‐ trum MMP inhibitor BB‐94 demonstrated a significant antitumour response in pre‐clinical pancreatic cancer models.[11] in clinical studies, the broad‐spectrum MMP inhibitors marimastat or tanomastat failed to show any significant clinical response.[12,13] The failure of the broad‐spectrum MMP9 inhibitors in clinical tri‐ als was mainly correlated with dose‐limiting side effects, a narrow therapeutic window as MMPs play a critical role in homeostatic processes 14 and general lack of efficacy in advanced tumour bur‐ den settings.[15,16] recently, the focus has been shifted towards more specific MMP inhibitors (such as MMP2 or 9 anti‐ bodies) that may have better efficacy and improved toxicity profile. Previous studies have shown the antitumour efficacy of AB0046 in pre‐clinical models of colorectal cancer 26 and encouraging clinical activity of andecalix‐ imab in combination with chemotherapy in gastric cancer.[27]
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